FI105068B - An accelerated and controlled release chewing gum composition - Google Patents

Abstract

A chewing gum composition with accelerated, controlled release of active agents comprising one or more active agents, a chewing gum base and optionally conventional auxiliary agents and additives. The chewing gum is prepared on the basis of a chewing gum base having a resin component containing at least 25 weight % of a particular resin. The accelerated, controlled release of the active agents is obtained by adding at least one solubilizer having an HLB of 14-20 in a quantity of 0.1-10 weight % to the chewing gum composition.

Description

105068

A chewing gum composition for accelerated and controlled release of active substances - Tuggummikomposition med accelererad, reglerad frisättning av aktiviva medel

TECHNICAL FIELD The present invention relates to an accelerated and controlled release chewing gum composition comprising one or more non-drug active ingredients and additives, a chewing gum base and optionally conventional excipients.

BACKGROUND OF THE INVENTION In recent years, great interest has been shown in providing methods for the controlled release of active ingredients from chewing gum. This widespread interest is due, in part, to the desire to use chewing gum as a delivery system, for example, to active agents, and partly to the ability to release expensive ingredients such as flavoring agents and highly effective (or potent) sweeteners in relatively short chewing cycles.

The release rate and the release rate of the gum are determined by many factors. The crucial property is the solubility of the substance. Thus, the substantially water-soluble substance is generally rapidly released, while the substantially fat soluble component is bound with varying strength to the water-soluble chewing gum components; the use of the latter substance results in slower and sometimes too little release during the normal chewing period.

The relative proportion of soluble and insoluble constituents in the chewing gum composition, the size of the chewing gum, and the chewing strength and salivation of the chewing gum 25 also significantly influence the release. Usually. · It is neither possible nor desirable to change the latter.

For this reason, it is necessary to use other methods in cases where it is desired to influence the release. In general, these methods seek to influence the rate of dissolution of the agent by using coatings, absorption or ad-30 sorption, or by encapsulating the agent in other materials. Hydrophilic compounds can be used in conjunction with substances with poor water solubility as a means of providing better and faster release. Examples of such relatively low solubility agents are, for example, flavorings and relatively sparingly soluble but highly sweetening sweeteners such as saccharin and aspartame.

A well-known problem in the manufacture of chewing gum is that only a small percentage of the added flavorings are released from the chewing gum during a normal refining period of 2 to 10 minutes. It is not uncommon for the amount of flavoring released, expressed as a percentage of the total amount of flavoring added, to be in the order of 5-15% after 2 minutes chewing 10-20% after 5 minutes chewing 7-20%.

This means that a very large proportion, 75-90%, of the added flavorings are wasted when the chewing gum is discarded. This is the reason that chewing gum uses a relatively large amount of flavoring agents compared to other sweets. Because flavoring agents are often expensive ingredients, their amount in the chewing gum composition, although typically in the range of about 0.5 to 2% in the chewing gum composition, greatly affects the price and, consequently, the competitiveness of the product.

Several methods have been provided for the preparation of a chewing gum composition capable of releasing specific components in a controlled manner. Thus, many manufacturing methods are known for better release of certain flavorings and very strong sweeteners and which are intended to prolong the taste sensation when chewing gum.

U.S. Patent 4,238,475 discloses a chewing gum comprising a water-insoluble therapeutic ingredient coated with a water-soluble coating agent to prevent the therapeutic component from re-absorbing into the chewing gum base. However, the release of the therapeutic agent is dependent on the coating remaining intact during chewing. As a result, the therapeutic component does not come into direct contact with the oral cavity and therefore cannot be used with drugs intended to act locally in the oral cavity and pharynx. In addition, the manufacturing process is complicated and further complicated by the fact that the coating must not be broken during manufacture.

EP-A-227 603 discloses a chewable delivery system comprising an active agent coated with lecithin, polyoxyalkylene, glyceride, etc., which, after coating, is combined with a matrix system consisting inter alia of gelatin, water 3105068 and a sweetener. Also in this case, the active agent continues to flow from the oral cavity in a coated form and therefore does not produce a local effect.

European Patent Application Publication No. 229,000 discloses a method and chewing gum for protecting and controlling the release of an active substance, including drugs, very strong sweeteners and flavorings. A hydrophobic coating is applied to the active agent using a molten mixture of polyvinyl acetate and a plasticizer, followed by cooling, grinding, screening and mixing with conventional chewing gum ingredients. It is mentioned in the publication that a delay of release in the order of 10 to 20 minutes can be achieved, but this does not automatically lead to an increase in the total amount of substances released. The process is quite complex and the active substance is required to withstand the temperatures used in the manufacturing process.

EP-A-217109 describes a chewing gum in which prolonged and controlled release of, inter alia, pharmaceutical substances, food additives and confectionery additives is achieved, for example, by means of cellulose compounds, polyvinylpyrrolidone, starch or sucrose, etc. However, the method is complex and difficult to control.

U.S. Patent Nos. 4,493,849 and 4,597,970 disclose that lecithin may be used in chewing gum to improve the mouth feel and to increase wetting properties and texture.

U.S. Patent 4,518,615 discloses a chewing gum base composition that does not adhere to dentures, removable and attached mouth prostheses, tooth sites, or natural teeth, said chewing gum base composition comprising from about 10% to about 30% elastomer, 2 to 18% elastomer by weight. , 15-45% polyvinyl acetate, 2.0-10% emulsifier, 0.5-15% low molecular weight polyethylene, 0.5-10% waxes, 10-40% plasticizer and 0-5% fillers.

DK Patent Application 5386/83 describes a method for providing a longer duration of action in the oral cavity for the treatment of oral fungal infections. This is accomplished by formulating fungicidal active agents, particularly imidazole and triazole derivatives, with specific gel-forming agents such as cellulose ethers, sodium alginate and propylene glycol alginate to improve adhesion of the active agent to the oral cavity. However, it is uncomfortable and it is difficult to hold such gelatinous preparations in the mouth for a long time and the effect of the active ingredient varies considerably depending on how long it is kept in the mouth.

U.S. Patent 4,541,382 describes a process for solubilizing the water-insoluble gingivitis, imidat-5-solyl-1,1- (p-chlorophenoxy) -3,3-dimethyl-2-butanone, for oral compositions. Oral compositions include mouthwashes, chewing gum, tooth powder and toothpaste, but only use in mouthwashes and toothpaste has been documented. If a person skilled in the art on the basis of the aforementioned U.S. Patent attempts to make a chewing gum using the indicated amounts of a solubilizer, most chewing gum base materials will find that the chewing gum base also becomes soluble, meaning that the chewing gum will disintegrate when chewed.

Thus, there is still a need for an acceptable chewing gum composition capable of delivering a relatively low soluble active ingredient so that it acts locally in the oral cavity and pharynx, or is absorbed through the oral mucosa, while still being comfortable to take or use if desired to provide a palatable effect. as in cases where the active ingredient is, for example, a flavoring agent.

It has been surprisingly found that it is possible to provide a chewing gum composition which releases the active ingredients in an accelerated controlled manner and which comprises one or more active ingredients, a certain selected chewing gum base and common excipients and additives.

DESCRIPTION OF THE INVENTION The chewing gum composition of the present invention is characterized in that the gum component of the chewing gum base comprises at least 25% by weight of a resin selected from terpene resins, glycerol ester of polymerized resin, pentaerythritol ester of a glycerol ester of a wood or rubber resin and high molecular weight polyvinyl acetate resins having a molecular weight of at least 30,000, and wherein at least one solubilizer is present in the chewing gum composition in an amount of 1-10% by weight, said solubilizer having an HLB value of 6-10; 14-20.

Thus, in accordance with the present invention, it has been found that it is possible to increase the release rate of substantially poorly water soluble substances as compared to the release from conventional compositions without the use of a solubilizer.

5 105068

It is generally assumed that only small amounts of surfactant can be added to the chewing gum and, from a theoretical point of view, it would be expected that the addition of larger amounts would generally result in very strong softening and dissolution of the entire chewing gum base. However, it has been found that this does not occur when * a base material containing at least 25% by weight of the above-mentioned particularly suitable resins is used as a gum base. In some cases, such chewing gum bases may themselves contain a low solubility surfactant, but usually only in low concentrations such as, for example, 0-12% by weight of the chewing gum base and usually 10-0-6% by weight thereof. Such surfactants, which generally act as emulsifiers, affect the chewing gum base by emulsifying water therein. It has been found that these emulsifiers have a weak solubilizing effect on the active ingredients added to the chewing gum, but this effect is usually minor compared to the effect obtained by the solubilizers used in the present invention. The amounts of solubilizers disclosed in this description do not include any surfactants that are conventionally already present in the chewing gum base used as starting material.

According to the present invention, it has been found that by using said chewing gum base, by simply mixing the solubilizing agent, or alternatively by simple premixing and without heating the mixture, it is possible to obtain a better release of the active ingredients without damaging it.

It has been found that the amount of solubilizing agent is the decisive factor in determining the predetermined degree of release of the active agent. In the case of active substances which are poorly released in the absence of solubilizing agent (for example, 10-40% by weight after chewing for 10 minutes), it is generally necessary to add more than 1% by weight of solubilizing agent to achieve a positive effect. In the case of active substances which are released very poorly without the addition of a solubilizer (for example, a few% by weight after 10 minutes of chewing), a significant increase in release is observed by the mere addition of 1% by weight of solubilizer. The upper limit for the amount of solubilizer to be added depends on the chewing gum formulation, the type of chewing gum base, the type and amount of active ingredient, and not the type of least solubilizing agent. Generally, it is not possible to add more than 30% by weight of solubilizing agent without rendering the chewing gum composition completely unacceptable, and generally such large amounts are not necessary or desirable as they often lead to excessively rapid release. Thus, the choice of type and amount of solubilizer will always depend on the type of active agent and the particular gum formulation in question. Experiments have shown that a good release is achieved at a solubilizing agent concentration of 1-10% by weight, preferably 3-6% by weight, without rendering the composition unacceptable.

A further advantage of the present invention is that the solubilizer used is generally a cheap ingredient which does not appreciably affect the price of the chewing gum composition at the concentrations used and does not require the purchase of expensive specialized equipment.

A further advantage of the chewing gum composition of the present invention is that it is now possible to prepare products having novel taste profiles and / or effects because of the release of active substances which, due to their low rate of release, were previously uneconomical or impossible to use and because they can be released in other tranches.

In addition, several solubilizing agents have already been approved for use in food or for use in pharmaceuticals.

It is known that by depositing the active ingredients in the chewing gum layer, a faster and higher release can be achieved than by the conventional method of adding the active ingredient to the core of the chewing gum. However, experience has shown that the use of this principle results in the fact that although most of the active substance is released, a large portion of said active substance is re-absorbed into the chewing gum base at the beginning of the chewing cycle, which overall provides only a relatively small benefit. during the first minute of the trip. On the other hand, the chewing gum composition of the present invention enables a more complete release over a longer chewing cycle and is also technically easier to add the active ingredient to the core of the chewing gum as compared to being added to the grain layer.

The scope of the present invention will be more fully apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples illustrating preferred embodiments of the present invention are provided for purposes of illustration only, as changes and modifications within the spirit and scope of the invention will be apparent to those skilled in the art from this detailed description. .

A particular embodiment of this chewing gum composition is characterized in that the gum component of the chewing gum base contains at least 40% resin, which may be 7105068 terpene resins, glycerol ester of polymerized resin, Penta-non- glycerol ester or high molecular weight polyvinyl acetate resin having a molecular weight of at least 30,000.

In another preferred embodiment, the chewing gum composition is characterized in that the gum component of the chewing gum base contains a terpene resin of natural or synthetic origin.

In principle, all types of surfactants for which toxicity is acceptable at the concentrations used can be used as solubilizers. As pre-10 examples of solubilizers used in the chewing gum compositions of this invention, reference is made to H.P. Fiedler, Lexikon der Hilfstoffe fur Pharmacie, Kosmetik und Angrenzende Gebiete, pp. 63-64 (1981) and country lists of approved food emulsifiers.

Both anionic, cationic, amphoteric and nonionic solubilizers can be used, but the commonly used solubilizer is either anionic or non-ionic, since mainly such solubilizers are approved for use in food. In those cases where the active agent is reactive, it is generally preferable to use a nonionic solubilizer since such agents are not very reactive and therefore do not adversely affect the stability of the active agent.

The choice of solubilizer should also take into account the fact that the taste of the solubilizer must be acceptable. Thus, it is natural to try to find suitable substances among the approved food emulsifiers and the approved emulsifiers for use in oral medications.

Suitable solubilizing agents include polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid esters, fatty acid salts of edible fatty acids, mono- and diglycerides and diacetyl tartaric acid esters of mono-, edible fatty acids, citric acid esters of mono- and diglycerides of fatty acids zag 30 karoosiesterit, polyglycerol esters of fatty acids, internally esterified polyglycerol risiiniöl-jyhapon (E476), sodium stearoyl lactylate, sodium lauryl sulfate, and sorbitan esters of fatty acids, which solubilizers are all known food emulsifiers, and polyoxyethylated hydrogenated castor oil (e.g. under the tradename CREMOPH POLOXAMER polymers for sale), polyoxyethylene fatty alcohol ethers, polyoxyethylene sorb Danish fatty acid esters, sorbitan esters of fatty acids and stearic acid ester of polyoxyethylene, all of which are known in the EEC as being used as pharmaceutical-cosmetic emulsifiers.

Particularly suitable solubilizing agents are polyoxyethylene stearates such as polyoxyethylene (8) stearate and polyoxyethylene (40) stearate, polyoxyethylene sorbitan fatty acid esters sold under the tradename TWEEN, e.g. TWEEN 20 (monolaurate), TWEEN 80 ), TWEEN 60 (monostearate) or TWEEN 65 (tristearate), edible mono- and diacetyl tartaric acid esters of mono- and diglycerides of edible fatty acids, citric acid esters of mono- and diglycerides of edible fatty acids, sodium stearoyl oxylate, sodium stearoyl lactate, block copolymers of propylene oxide, polyoxyethylene fatty alcohol ethers. The solubilizing agent may be either a single compound or a combination of several compounds. The term "solubilizer" is used herein to describe both possibilities, the solubilizer used must be suitable for use in food.

It has been found that there may be a relationship between the solubility profile of the active substance and the HLB value of the solubilizer used. However, it has not been possible to establish a correlation between the solubility parameters of the active agent and the HLB of the solubilizer. In practice, it has been found that generally a good effect is achieved by the use of a solubilizing agent having an HLB value of 14 to 20, preferably 14 to 18. However, a good effect is also obtained with solubilizing agents having an HLB value is between 6 and 10, preferably 7-8. The HLB values used in this specification and claims are taken from the literature or are based on information provided by the manufacturer. For definitions of HLB values and examples of HLB values for various solubilizers, reference is made to the above H.P. Fiedler, Lexikon der Hilfstoffe fur Pharmacie, Kosmetik und Angrenzende Gebiete, pp. 65-69 (1981).

The chewing gum base for use in the chewing gum of this invention is generally prepared by conventional heating and mixing of various ingredients such as elastomers, resins, inorganic fillers, waxes, fats and emulsifiers, etc.

105068 9

Any conventional elastomer may be used in an amount typically from 3 to 25% by weight. The elastomer may be derived from nature, such as those disclosed in the Food and Drug Administration, CFR, Title 21, Section 172.615, as naturally occurring chewable substances 5 ("Masticatory Substances of Natural Vegetable Origin"), the elastomer may be synthetic. , such as styrene-butadiene rubber (SBR), butyl rubber (a copolymer of isobutylene and iso-prene) or polyisobutylene (as mentioned in the FDA publication Masticatory Substances, Synthetic).

The inorganic fillers which form part of the chewing gum base may be present in an amount of up to 50% by weight, preferably 0-30% by weight. Suitable excipients include calcium carbonate, talc, sodium sulfate, alumina, magnesium carbonate, kaolin, silica and calcium phosphates, alone or in a mixture of several substances. Conventionally, waxes and fats are used to adjust the composition and softness of the chewing gum base. Any conventionally used and suitable wax, such as rice bran wax, polyethylene wax, petroleum wax (refined paraffin and microcrystalline wax), paraffin wax, beeswax, camauba wax, candelilla wax, cocoa butter, non-fat cocoa powder and any suitable oil, e.g. wholly or partially hydrogenated vegetable oils; or animal fat, wholly or partly hydrogenated. The amount of wax used may range from 0 to 50% by weight.

One or more emulsifiers can usually be added to further soften the chewing gum base and obtain water-binding properties, ** which makes the surface of the chewing gum base a pleasantly smooth surface and reduces its tendency to adhere. Examples of legal and conventional emulsifiers to be added to the base of chewing gum include mono- and diglycerides of edible fatty acids, lactic and acetic acid esters of mono- and diglycerides of edible fatty acids, Mg-sugars, , hydroxylated lecithin and *. 30 other similar substances.

As previously mentioned, said emulsifiers, which are conventionally used in an amount of 0-12% by weight and preferably 0-6% by weight of the chewing gum base, may have a solubilizing effect on the active ingredient which is subsequently added to the chewing gum prepared using such an emulsifier. . However, this effect is usually minor when compared to the solubilizing agents which, according to practice of this invention, are usually added during chewing gum preparation and not into the chewing gum base.

In addition, the gum base may contain common additives such as antioxidants, for example BHT, BHA, propyl gallate and tocopherols, as well as preservatives and coloring agents.

Resins should also be mentioned as constituents of the chewing gum base, where such resins are necessary to obtain the correct chewing composition and as solubilizers of the elastomers of the chewing gum base.

As mentioned above, the resin used has significance in the chewing gum composition according to the present invention. Thus, it has been found that not all conventionally used resins can be used in a gum base, which is also intended to be used in a gum containing a solubilizer.

Thus, the addition of even a small amount of solubilizing agent, for example 0.5% by weight, often causes the chewing gum composition to become unacceptable, for example, either by becoming unusually soft or, in most cases, by completely disintegrating in the first chewing process. in minutes.

However, it has been found that this can be avoided if at least 25% of the total resin content comprises one or more of the following basic resins: natural or synthetic terpene resins (such as α- and β-pinene, dipentene or delta limonene), glycerol ester of a polymeric resin, pentaerythritol ester of wood or rubber resin, pentaerythritol ester of partially hydrogenated wood or rubber resin, pentaerythritol ester of partially hydrogenated wood or rubber resin, or high molecular weight polyvinyl 25 acetate, having a molecular weight greater than 30,000.

As mentioned, said base resins must constitute at least 25%, in particular 40%, of the total gum base gum in order for the gum base properties to be acceptable. The gum base may contain one of the base resins or a mixture of two or more base resins.

In addition to the above condition that at least 25% by weight of said base resins must be present, any conventionally used resin may be used in the chewing gum base, including a glycerol ester of a wood or rubber resin, a glycerol ester of a partially dimerized resin, polyvinyl acetate, i.e., having a molecular weight of less than 30,000.

It will, of course, be clear to one skilled in the art that the exact minimum amount of base resins required may depend on many different conditions for both the chewing gum base and the chewing-5 min formulation.

For example, if mainly low molecular weight elastomers and a large amount of plasticizers, greases and waxes are used, it is often necessary to use a greater amount of base resins to provide a satisfactory solid chewing gum.

Yet another embodiment of the composition of the present invention is characterized in that it further comprises up to 60% by weight of at least one carrier, which carrier (s) form a solid dispersion with the active agent.

The carrier used to form the solid dispersion may be any material that has been found useful for this purpose, for example, one of polyethylene glycols, urea, polyvinylpyrrolidone, sweeteners such as sorbitol, xylitol, mannitol, sugar and dextrose, citric acid and succinic acid. lactic acid or one of its derivatives, one of sterols or the like, one of surfactants, one of pentaeythritol or one of the like spherical compounds, one of polymers, and urethane, one of a fatty acid compound such as glyceryl oleate, cyclodextrin, succinamide, sodium citrate, any of dextrans, methylcellulose, sodium alginate, gelatin, carrageenan, pectin, sodium carboxymethylcellulose, polyvinyl alcohol, acacia, tragacanth, guar gum or any combination thereof, preferably pol ethylene glycol or polyvinylpyrrolidone, particularly preferably polyethylene glycol having a molecular weight of 1000 to 20,000, especially polyethylene glycol having a molecular weight of 6,000. A single carrier or, if possible, a combination of several carriers may be used. The term "carrier" is used herein to describe both possible. suutta.

The process for preparing the solid dispersion may be one of the methods that have been shown to be suitable for this purpose. For example, the active substance and the carrier may be thawed together and then cooled briefly. The mixture is then ground and screened to the desired particle size. Alternatively, the active substance and the carrier are dissolved in a liquid which is evaporated to give a precipitate of the active ingredient and the carrier, said mixed precipitate being optionally ground and screened. Of these processes, the former, also referred to as the thawing process, is often advantageous because the solvents used in the latter process are often hazardous to health and should therefore be avoided.

The present invention has proven to be advantageous for the controlled release of active agents which may be dietary supplements, oral and dental compositions, antiseptics, acidity regulators, smoking cessation agents, sweeteners, flavorings, caffeine, chlorhexidine diacetate, 1,8-cineole, aspartame, sodium fluoride, nicotine, saccharin, quaternary ammonium compounds, vitamin E, vitamin A, vitamin D, sodium bicarbonate, active ingredients derived from ginkgo, propolis , the active components of ginseng or peppermint oil.

The active agents used in the present invention may be any substance other than the drug desired to be released from the chewing gum. Active substances for which accelerated release is desired are primarily substances with low water solubility, typically less than 10 g / 100 ml, including substances which are wholly insoluble in water. Examples include dietary supplements, oral formulations, smoking cessation agents, very strong sweeteners, acidity regulators, flavorings, etc.

Examples of dietary supplements as active ingredients are, for example, salts and compounds having a nutritional effect of vitamin B2 (riboflavin), vitamin B12, folic acid, niacin, biotin, poorly soluble glycerophosphates, amino acids A, D, E Vitamins K and minerals in the form of salts, complexes and compounds containing calcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese, chromium, selenium, molybdenum, potassium, sodium or cobalt.

Reference is also made to lists of nutrients approved by the authorities of different countries, such as US Code of Federal Regulations, Title 21, Section 182.5013.182 30 5997 and 182.8013 to 182.8997.

Examples of active ingredients for oral and dental care and treatment include, for example, chemically bonded hydrogen peroxide and compounds capable of liberating urea during chewing.

, 3 105068

Examples of active antiseptic agents are, for example, salts and guanidine and biguanidine compounds (e.g. chlorhexidine diacetate) and the following types having low water solubility: quaternary ammonium compounds (e.g. ), dequaline compounds, polynoxylin, phenols (e.g., thymol, parachlorophenol and cresol), hexachlorophene, salicylanilide compounds, triclosan, halogens (iodine, iodine transport agents, chloramine and dichlorocyanuric acid salts) methyl alcohol, benzyl alcohol, phenoxyethanol and phenylethanol), cf. furthermore, 10 Martindale, The Extra Pharmacopoeia, 28th Edition, pages 547-578, salts of water-insoluble metals, complexes and compounds such as aluminum salts (e.g., aluminum potassium sulphate A1K (SC> 4) 2 · 12H2O) and boron should also be included, complexes of barium, strontium, iron, calcium, zinc (zinc acetate, zinc chloride and zinc gluconate), copper (copper chloride and copper sulfate), lead, silver, magnesium, sodium, potassium, lithium, molybdenum and vanadium, compositions for oral and dental care, such as fluorine-containing complexes and compounds (such as sodium fluoride, sodium monofluorophosphate, aminofluoride, and tin fluoride), phosphates, carbonates, and selenium.

In addition, compare J. Dent. Res., Vol. 28, No. 2, pp. 160-171 (1949), containing 20 of the large number of compounds studied.

Examples of the oral cavity pH adjusting agents are, for example, acceptable acids such as adipic acid, succinic acid, fumaric acid or its salts or citric acid, tartaric acid, malic acid, acetic acid, lactic acid and glutaric acid, phosphoric acid, such as sodium, potassium, ammonia, magnesium or calcium, especially magnesium and calcium carbonates, bicarbonates, phosphates, sulfates or oxides.

Examples of active smoking cessation agents are, for example, nicotine, tobacco powder or silver salts, for example, hoacetate, silver carbonate and silver nitrate.

Examples of sweeteners as active ingredients are, for example, so-called very potent sweeteners such as saccharin, cyclamate, aspartame, thaumatin, divethycalcones, stevioside, glycyrrhizine or its salts and compounds.

Other examples of active ingredients include, for example, any type of flavoring agent.

105068 14

Another particularly preferred preparation of the present invention comprises up to 50% by weight, preferably 0.1 to 10% by weight, of the active ingredient as a solid dispersion in a carrier, up to 60% by weight, preferably about 20% by weight, of a carrier. used to obtain a solid dispersion, 1-10% by weight of a solubilizer, 15-80% by weight, preferably about 35% by weight of chewing gum base and up to 85% by weight, preferably about 35% by weight, of adjuvants and additives.

A particularly preferred preparation of the present invention comprises up to 50% by weight, preferably 0.1 to 10% by weight, of 10 active ingredients mixed with a solubilizer, 15 to 80% by weight, preferably about 35% by weight, of chewing gum base, up to 85%. by weight, preferably about 50 to 60% by weight, of auxiliaries and additives, and from 1 to 10% by weight, preferably about 5% by weight, of a solubilizer.

In the chewing gum composition of the present invention, it is possible to use any of the auxiliaries and additives commonly used in chewing gum as additives and additives. Examples of these are sweeteners, flavorings, colorings and softeners, and consistency control agents.

Sweeteners useful in the chewing gum composition include, for example, sorbitol, xylitol, mannitol, palatinitol, malbitol, lactitol, hydrogenated glucose syrup, sucrose, glucose syrup, fructose, dextrose, lactose, sorbose and succinic acid, , thaumatin, glycymcine, divethyl chalcones and their salts and derivatives. The choice of sweetener or sweeteners will depend in part on whether or not a sugar-free product is required, and partly on the kind of composition and sweetness required for the composition of the present invention.

25 It is possible to use smaller amounts of the conventionally used very potent sweeteners because of their increased release.

Suitable flavoring agents for the chewing gum composition include, for example, natural or synthetic flavoring agents (including naturally occurring flavoring agents), such as aromatic oils, essences, extracts, powders, including acids and other substances capable of affecting the flavor profile.

Examples of liquid and powdery flavors are coconut, coffee, chocolate, vanilla, grapefruit, menthol, licorice, anise, apricot, caramel flavor, honey * aroma, pineapple, strawberry, raspberry, tropical fruit, cherry, cinnamon, peppermint, Gaul oil, green mint, eucalyptus and mint. As mentioned above, in many cases smaller amounts of the flavoring agent may be used.

There are no specific requirements for natural or synthetic dyes, except that they must be approved for use in food.

Glycerol, propylene glycol, lecithin, triacetin, hydrogenated glucose syrup, 70% sorbitol, glucose syrup, waxes and oils may be mentioned as suitable plasticizers or composition regulators for the composition of the present invention. These give the product a composition which is pleasant to chew during the desired 10 chewing cycles.

The formulation of the chewing gum base will depend on the type of chewing gum desired or the type of structure meeting the requirements set forth above. Raw materials suitable for chewing gum base include U.S. Pat. Substances according to Chewing Gum Base Regulations - Code of Federal Regulations, Title 21, Section 172.615 15.

A particular benefit of the present invention is that the chewing gum composition may be prepared using conventional materials, conventional devices and conventional manufacturing methods.

When the active ingredient is incorporated into the gum base, this product can be of any known type, such as lumps, which may alternatively use granules, or sheets or any other form of gum. The chewing gum pieces may be coated with a wax, a film coating or a conventional so-called caramel coating based on sugar-containing or sugar-free substances.

A single piece of chewing gum typically weighs 0.4 to 20.0 g. The following table shows 25 preferred thresholds for different product types:

Chewing gum pieces 500 - 3,500 mg Coated chewing gum 600 - 6,000 mg Chewing gum sheets 1,000 - 3,000 mg

Where the individual constituents of the chewing gum composition of the present invention are mentioned in the unit, this reference also includes a combination of several such agents, except where a particular ingredient is mentioned.

105068 16

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be illustrated in more detail using examples which do not limit the present invention.

EXAMPLES 5 General Methods

Manufacture of chewing gum base

Chewing gum base is made from the following ingredients:

4% by weight of elastomers

Terpene resin 28% by weight 10 Small molecule PVA 29% by weight

Emulsifier 8% by weight

Waxes 31% by weight

The elastomer is ground in a conventional chewing gum and gum base mixer while heated to 110-130 ° C and slowly added in small portions of terpene resin and small molecule PVA. Finally, waxes and emulsifier are added. To ensure a homogeneous base, it is important that all ingredients are added in small batches and that subsequent batches are not added until the preceding batch is comminuted.

It has been found that the resulting chewing gum base does not decompose when added to the solubilizer.

Manufacture of chewing gum

The chewing gum shown in the examples is formulated using the following basic formulation: 105068 17

Basic Phonation 1

Chewing gum base 35% by weight

Sorbitol powder 10% by weight

Hydrogenated glucose syrup 10% by weight 5 Active ingredient 0.01 to 30% by weight

Solubilizer 1-10% by weight

1.9% by weight of alternative flavoring

Alternatively, sorbitol powder q.s. 100% by weight

Bits of chewing gum are prepared in a manner conventionally used in the manufacture of chewing gum and using equipment commonly used in the manufacture of chewing gum.

The chewing gum base is melted or ground in a conventional chewing gum mixer. When the base mass of the chewing gum is homogeneous, the other ingredients are mixed one at a time in said stiffener. The solubilizing agent and the active agent may be added separately or as a premix or solution. Depending on the state of the ingredients and their melting point, such premix may be a simple mixture of one or more powders, a mixture of one or more powders in one or more liquids, or a mixture of several liquids at ordinary, higher or lower temperatures. In order to ensure proper dispersion of the ingredients, it may be advantageous, if possible, to add these substances as a liquid mixture or solution, especially when adding very small amounts of one or more components of the premix.

It is also possible to prepare a premix or solution containing the active ingredient and the solubilizing agent by combining these with other ingredients of the formulation, such as hydrogenated glucose syrup, flavoring agent, sorbitol or the actual gum base, if considered appropriate.

Except that the chewing gum base is first blended, the blending sequence is not absolutely accurate. However, the mixing time after the addition of the active substance should be of sufficient duration to ensure that these substances are sufficiently dispersed in the chewing gum mass. Optional flavorings are usually added last and then mixed for a further 2-3 minutes.

The Kim mixing step is completed, the homogeneous chewing gum mass is removed from the mixer, and cut and left to cool in small pieces or extruded into a thin sheet which is passed through a cooling device. The cooled 105068 18 mass is then extruded into a thin sheet which is rolled in a conventional chewing gum Vals curing system and cut into pieces of suitable shape and size.

The pieces are left to cure for two to five days, after which they are separated by shaking in a conventional cooking vessel. The pieces vii-5 are then finished by applying a layer of film coating or granule coating on them.

In the following Examples 1 to 46, 800 mg of chewing gum pieces are cut and coated with a thin layer of sorbitol with some flavoring added. The weight of each chewing gum is then 820 mg.

The release of the active substance in Examples 1 to 46 is determined under either in vitro or in vivo conditions.

In vitro conditions

In vitro experiments are performed in a chewing machine (L. Christrup, et al., Arch. Pharm. Chem. Sci. 14 (1986) pp. 30-36) by allowing one 820 mg chewing gum to remain in the chewing machine for 30 minutes in phosphate buffer solution. with a pH of 7.4. The results in the tables show the relative release of the active agent, with the release achieved without using the solubilizing agent set at 100%.

In vivo conditions

In vivo tests are performed by chewing the subject for 20, 2 and 5 minutes, followed by analyzing the remaining amount of active substance in the chewed piece to determine the amount released.

Also, the results obtained under in vivo conditions show a relative release, with the release achieved without the use of a solubilizer being set at 25 100%.

Examples 1-10

The monoglyceride diacetyl tartaric acid ester, PANODAN 165, prepared by Grindsted Products A / S, Denmark, used as a solubilizer, HLB7, was studied in vivo in chewing gum compositions as described above. The results are shown in Table 1.

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Table 1 19

EXAMPLE PANODAN Active Substance Concentration Relative Release at # 165 Weight -% ___% ____ _____2 min. 10 min 30 min

1 __5__MENTOLI__1,3 37 100 123 2 __0__MENTOLI__1,3 100 100 100 3 __5__1,8-SINEOLI 1.0__10 178 4 __0__1,8-SINEOLI 1.0 100 100 100 5 __5__ANETOLI__0,2 16__109 6 __0__ANETOLI__0,2 100 100 100 7 __5__KAR , 5 135 201 202 8 __0__CARVONI__0.5 100 100 100 9 __5__CAPHEINI__4.4 233 157 137 10 0 CAFFEINE 4.4 100 100 100

Examples 11-14

The 5 monoglyceride lactic acid ester Lactodan B30 from Grindsted Products A / S, used as a solubilizer, was studied in vivo in chewing gum compositions as described above. The results are shown in Table 2.

Table 2 ... Example LACTODAN Active substance Concentration Relative release kin.o B30 wt%% ______% ____ _____2 min. 5 min 10 mins, 11 5 CHLORINEHEXIDII, 625 155 108 103 ___NIDIACETATE ACID_____ 12 0 CHLORIDEHEXIDII, 625 100 100 100 ___NIDIACETATE_____ 13 __5__MENTOLI__1,300 156 120 14 | 0 MENTOLI_ 1,3 100 100 100 105068 20

Examples 15-34

The polyoxyethylene sorbitan fatty acid ester used as a solubilizer, TWEEN 60, was studied in vivo in chewing gum compositions as described above. The results are shown in Table 3.

5 Table 3

EXAMPLE TWEEN 60 Active substance Concentration Relative release at least weight -% ___%% ____ _____2 min. 5 min 10 min

15 __5 MENTOLI__1.3 348 392 188 16 __3 MENTOLI__1.3 226 235 157 17 __1 MENTOLI__1.3 109 146 61 18 __0 MENTOLI__1.3 100 100 100 19 __5 1,8-SINEQLI 1,0 201 152 107 20 __0__1.8- SINEOLl 1.0 100 100 100 21 __5 ANETOL1__0.2 202 173 129 22 __0 ANETOLI__0.2 100 100 100 23 5 SODIUM 0.075 160 145 125 ___FLUORIDI_____ 24 0 SODIUM 0.075 100 100 100 ___FLUORIDI_____ 25 __5 COFFEE I__4.4 300 210 190 26 __3 CAFFEINE__4.4 210 190 190 27 __1 CAFFEINE__4.4 125 115 160 28 __0 CAFFEINE__4.4 100 100 100 29 __5 NICOTININ__0.25 250 210 160 30 __0 NICOTININ__0.25 100 100 100 31 __5 SACCHARIN 0.1__U 370 200 32__U 370 200 , 1 100 100 100 33 __5 ASPARTAM 0.1 247 141 81 34 | 0 | ASPARTAM 0.1 1 100 1 100 100

Examples 35-40

The block copolymer of ethylene oxide and propylene oxide, PLURONIC L64, used as a solubilizing agent, was studied in vivo under chewing gum composition as described above. The results are shown in Table 4.

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Table 4

EXAMPLE PLURONIC Active substance Concentration Relative release also L64 weight -% ___ mouth% ___ _____2 min. 5 min LOM.

35 __5__MENTOLI__0.9 95 122 149 36 __0__MENTOLI__0.9 100 100 100 37 __5__1.8-SINEOLI 1.0 76 108 117 38 __0__1.8-SINEOLI 1.0 100 100 100 39 __5__ANETOLI__0.2 87 109 95 40 | 0 ANETOLI 0.2 100 100 100

Examples 41-46

CREMOPHOR RH 40 hydrogenated polyoxyl-540 castor oil used by BASF as a solubilizer was studied in vivo in chewing gum compositions as described above. The results are shown in Table 5.

Table S

EXAMPLE CREMOPHOR Active substance Concentration Relative release kin # RH 40 wt%% ___%% ____ _____2 min. 5 min 10 min, 41 __5__MENTOLI__0.9 144 155 123 42 __0__MENTOLI__0.9 100 100 100 43 __5__1.8-SINEOLI 1.0 156 138 104 44 __0__1.8-SINEOLI 1.0 100 100 100 45 __5__ANETOLI__0.2 124 120 84 46 0 ANETOLI 0.2 100 100 100 • <m «

Claims (12)

1. Chewing gum composition with accelerated, controlled release of active agents comprising one or more active agents not constituted by drugs, and additives, a chewing gum base and any common aids, characterized in that the resin component of the chewing gum base contains at least 25% by weight of a resin selected from terpene resins, glycerol esters of polymerized rosin, pentaerythritol esters of wood or rubber rosin, pentaerythritol esters of partially hydrogenated wood or rubber rosin, glycerol esters of partially hydrogenated wood or rubber rosin acrylate and high molecular weight polyethylene acrylate and high vinyl polyethylene polyacrylate and that at least one solubilizer in an amount of 1 - 10% by weight has been added to the chewing gum composition, the solubilizer having an HLB value of 6-10 or 14-20. Chewing gum composition according to claim 1, characterized in that the resin component of the chewing gum base contains at least 40% of a resin selected from terpene resins, glycerol esters of polymerized rosin, pentaerythritol esters of wood or rubber rosin, pentaerythritol esters of partial or hydrolyzate wood or rubber rosin and high molecular weight polyvinyl acetate resins with a molecular weight of at least 30,000. Chewing gum composition according to claim 1, characterized in that the resin component of the chewing gum base contains a terpene resin of natural or synthetic origin. Chewing gum composition according to claim 1, characterized in that the solubilizing agent in the composition is selected from polyoxyethylene sorbitan fatty acid esters, fatty acid salts, mono- and diacetyltartaric acid esters of mono- and diglycerides of edible fatty acids and citric acid esters of monoacetic acid esters, fatty acids; polyglycerol esters of fatty acids; Chewing gum composition according to claim 4, characterized in that the solubilizing agent is polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, mono- and diacetyltartaric acid esters of mono- and diglycerides of edible fatty acids, citric acid esters of mono- and diglycerate acids, Chewing gum composition according to claim 1, characterized in that 3 to 6% by weight of solubilizing agent is added to the chewing gum composition. Chewing gum composition according to claim 1, characterized in that the composition further contains up to 60% by weight of at least one carrier which (s) forms a solid dispersion together with the active agent. Chewing gum composition according to claim 7, characterized in that the carrier is selected from polyethylene glycol and polyvinylpyrrolidone. Chewing gum composition according to claim 8, characterized in that the carrier is polyethylene glycol having a molecular weight of 1,000-20,000. Chewing gum composition according to claim 1, characterized in that the active agent (s) has less water solubility than 10 g / 100. 10. U18 lauryl sulfate, polyoxyethylated, hydrogenated castor oil, block copolymers of ethylene oxide and propylene oxide or polyoxyethylene fatty alcohol ether. Chewing gum composition according to claim 10, characterized in that the active agent is selected from the group consisting of dietary additives, oral and dental compositions, antiseptics, pH-adjusting agents, anti-smoking agents, sweeteners, flavors or flavorings. Chewing gum composition according to claim 11, characterized in that the active agent is selected from menthol, carvone, caffeine, chlorhexidine diacetate, 1,8-cineol, asparagine, sodium fluoride, nicotine, saccharin, quaternary ammonium compounds, vitamin E, vitamin, vitamin D, sodium hydrogen carbonate, the active components from ginkgo, the active components from propolis, the active components from ginseng or peppermint oil.